2024 Theses Doctoral

Deciphering the Roles of Nuclear Envelope Proteins Associated with Emery-Dreifuss Muscular Dystrophy in the Heart

Jin, Qi

Mutations in the gene encoding the nuclear lamina protein lamin A/C (LMNA) and the associated integral inner nuclear membrane protein emerin (EMD) give rise to similar disease phenotypes and are both classified as Emery-Dreifuss muscular dystrophy (EDMD). However, the connection between the function of these nuclear envelope proteins and disease phenotype remains elusive.

Given the consistent manifestation of dilated cardiomyopathy in EDMD, my investigation focused on deciphering the roles of these nuclear envelope proteins in the heart. To better understand their functions, I generated a set of isogenic human induced pluripotent stem cell (iPSC) lines with either LMNA mutation causing lamin A/C haploinsufficiency or EMD mutation causing emerin deficiency. I differentiated these iPSCs into cardiomyocytes (iPSC-CMs) and obtained their RNA transcript and protein expression profiles.

I found that both mutant lines exhibited significant overlap in transcriptome and proteome changes. Analyzing alterations at both RNA and protein levels shed light on the potential functional roles of lamin A/C and emerin in cardiomyocytes and pathogenic mechanisms. To better understand the cardiac defects caused by loss of lamin A/C. I generated mice lines with tissue-specific and temporally regulated knockout of Lmna in the heart. The mutant mice experienced lethality due to heart failure, regardless of whether Lmna was knocked out at the embryonic or mature adult heart. This demonstrates that lamin A/C has a vital role in the normal function of cardiomyocytes.